In order to fully understand changes in brain function during aging, it is necessary to understand how hormones that decline with age normally regulate and maintain structural and functional plasticity and resilience of the adult brain. Estradiol (E) is the best studied hormone with respect to cognitive decline and Alzheimer's disease. Yet, even then, we are largely ignorant about how the aging brain responds to E at the cellular, molecular and anatomical levels and how E regulated plasticity and neuroprotective actions may change with age. Moreover, we need to know whether E has neuroprotective actions that are related to their ability to regulate structural and functional plasticity and to contain the production in brain of potentially damaging molecules such as cytokines that rises with age. The main objective of this project is to carry out in vitro studies of the signaling pathways at the cellular and molecular level by which E causes synapse formation in hippocampal and cortical neurons and also protects cells against damage and death. The main hypothesis is that E-induction of dendritic spines is a mechanism that not only enhances neural function and memory processes but also confers protection of neurons from excitotoxic damage, in part because both involve operation of the same signaling pathways. Collaborative studies will determine the relevance of these mechanisms to the studies of the hypothesized age-related decline in E-induced synapse formation in the aging rat and primate brain which are being studied in other components of this program project. The E-regulated signaling pathways increase the options for intervention by estrogens or modified estrogens. Because hormone therapy (HT) is under close clinical scrutiny, it is critical to obtain a more detailed, mechanistic understanding of how estrogens affect the brain in order to provide for more informed approaches to HT and to promote an understanding of successful brain aging. Results from this project and from the PPG as a whole should facilitate identification of specific analogs and other pharmacologic molecules of therapeutic value to the aging process.